NM_000625.4:c.-73-10C>T

Variant names:

• chr17-27798892-G-A
• rs3730013
• NM_000625.4:c.-73-10C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000625.4(NOS2):​c.-73-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 886,886 control chromosomes in the GnomAD database, including 53,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (8780 hom., cov: 31)
  • Exomes 𝑓: 0.35 (44784 hom.)
• Consequence: NOS2 NM_000625.4 intron
• Scores: Splicing: ADA: 0.0001112
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.663
• Publications: 23 publications found

Genes affected

NOS2 (HGNC:7873): (nitric oxide synthase 2) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. This gene encodes a nitric oxide synthase which is expressed in liver and is inducible by a combination of lipopolysaccharide and certain cytokines. Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

NOS2 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000266202 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-27798892-G-A is Benign according to our data. Variant chr17-27798892-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.-73-10C>T		intron_variant	Intron 1 of 26	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.-73-10C>T		intron_variant	Intron 1 of 26	1	NM_000625.4	ENSP00000327251.6
ENSG00000266202	ENST00000582441.1	c.439-10C>T		intron_variant	Intron 4 of 4	4		ENSP00000462879.1
NOS2	ENST00000697337.1	n.-83C>T		upstream_gene_variant				ENSP00000513259.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51076 AN: 151856 Hom.: 8777 Cov.: 31

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.367 AC: 76702 AN: 209188 AF XY: 0.366

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.361

Gnomad EAS exome AF: 0.329

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.348 AC: 255688 AN: 734912 Hom.: 44784 Cov.: 10 AF XY: 0.350 AC XY: 136515 AN XY: 390148

African (AFR) AF: 0.308 AC: 6101 AN: 19812

American (AMR) AF: 0.470 AC: 18658 AN: 39680

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 7435 AN: 20758

East Asian (EAS) AF: 0.354 AC: 12820 AN: 36228

South Asian (SAS) AF: 0.408 AC: 28123 AN: 68858

European-Finnish (FIN) AF: 0.329 AC: 16437 AN: 49984

Middle Eastern (MID) AF: 0.404 AC: 1763 AN: 4366

European-Non Finnish (NFE) AF: 0.331 AC: 151845 AN: 458622

Other (OTH) AF: 0.342 AC: 12506 AN: 36604

GnomAD4 genome AF: 0.336 AC: 51116 AN: 151974 Hom.: 8780 Cov.: 31 AF XY: 0.341 AC XY: 25320 AN XY: 74288

African (AFR) AF: 0.305 AC: 12627 AN: 41418

American (AMR) AF: 0.407 AC: 6213 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1225 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1628 AN: 5170

South Asian (SAS) AF: 0.424 AC: 2034 AN: 4800

European-Finnish (FIN) AF: 0.324 AC: 3425 AN: 10562

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22906 AN: 67962

Other (OTH) AF: 0.330 AC: 697 AN: 2110

Alfa AF: 0.336 Hom.: 13239

Bravo AF: 0.338

Asia WGS AF: 0.374 AC: 1302 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 51% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.53
PhyloP100		0.66
PromoterAI		0.0053	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3730013; hg19: chr17-26125918;